HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 3, 2010, pp. 675-688
Received, 24th December, 2009, Accepted, 26th January, 2010, Published online, 28th January, 2010.
DOI: 10.3987/COM-09-11894

■ Synthesis of Fused Thiopyranthione and Thiophene Derivatives from 4,5-Dihydro-3-thiophene(and -3-furan)carbonitriles Having an Active Methylene Group at C-2 Position

Hiroshi Maruoka,* Fumi Okabe, Keishi Yamasaki, Eiichi Masumoto, Toshihiro Fujioka, and Kenji Yamagata

Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

A versatile strategy is described for the synthesis of new fused thiopyranthione and thiophene derivatives. The reaction of heterocyclic α,β-unsaturated nitriles 3a−c, 4a−d, 5a−c, and 6a−d, which were prepared from tetrahydro-2-oxo-3-thiophene- and -3-furan-carbonitriles 1a−c and/or 2a−d and alkylidene phosphoranes such as (triphenylphosphoranylidene)acetonitrile and methyl (triphenylphosphoranylidene)acetate through Wittig reaction, with carbon disulfide in the presence of sodium hydride in THF gave the corresponding 6-thioxothieno[3,2-c]thiopyran and 6-thioxothiopyrano[4,3-b]furan derivatives 7a−c, 8a−d, 9a−c, and 10a−d. On the other hand, treatment of compounds 3a−c, 5a−c, and 6a−d with sulfur powder in the presence of triethylamine in methanol caused Gewald reaction to provide the corresponding thieno[3,4-b]thiophene and -furan derivatives 11a−c, 12a−c, and 13a−d.

INTRODUCTION
Heterocycles and heterobicycles form, by far, the largest of the classical divisions of organic chemistry.1−6 Moreover, they are of immense importance not only biologically and industrially but also to the functioning of any developed human society as well. The majority of pharmaceutical products that mimic natural products with biological activity are heterocycles. Therefore, researchers are on a continuous pursuit to design and produce better pharmaceuticals, pesticides, insecticides, rodenticides, and weed killers by natural models. It is easy to understand why both the development of new methods and the strategic development of known methods for the synthesis of heterocyclic compounds continue to drive the field of synthetic organic chemistry. Organic chemists have been engaged in extensive efforts to produce these heterocyclic compounds by developing new and efficient synthetic transformations. Among them, cyclocondensation reactions are of the most attractive methodologies for synthesizing heterocyclic compounds, and the need for improved cyclocondensation reactions is evident.
In the course of our studies on heterocyclic β-enaminonitriles,7−11 we became interested in the development of the methods for the synthesis of heterobicycles such as thieno[3,2-c]thiopyrans,12,13 thiopyrano[4,3-b]furans,14 thieno[3,4-b]thiophenes,15−17 and thieno[3,4-b]furans. The synthesis of these compounds has been rarely described in the literature. Therefore, there is a need for synthetic methods suitable for their analogues. As part of our current studies on the development of new routes in heterocyclic synthesis, we herein describe an efficient procedure for the synthesis of fused thiopyranthione and thiophene derivatives 7−13 from the reactions of heterocyclic α,β-unsaturated nitriles 3−6 as one of versatile starting materials and carbon disulfide and/or sulfur powder in the presence of sodium hydride or triethylamine.

RESULTS AND DISCUSSION
Initially, we examined Wittig reaction of tetrahydro-2-oxo-3-thiophene- and -3-furan-carbonitriles 1a−c and 2a−d with alkylidene phosphoranes (Scheme 1). Compounds 1a−c and 2a−d were easily prepared by treatment of 2-amino-4,5-dihydro-3-thiophene- and -3-furan-carbonitriles with hydrochloric acid according to our previous procedure.18−21 Furthermore, we have also shown Wittig reaction of compounds 1a and 2a with (triphenylphosphoranylidene)acetonitrile (entries 1 and 4 in Table 1).22 Thus, the starting materials, heterocyclic α,β-unsaturated nitriles 3a−c, 4a−d, 5a−c, and 6a−d were synthesized by Wittig reaction of compounds 1a−c and 2a−d with (triphenylphosphoranylidene)acetonitrile and/or methyl (triphenylphosphoranylidene)acetate in refluxing toluene with 55−98% isolated yields (Scheme 1 and Table 1). Elemental analyses, MS spectra, 1H and 13C NMR spectra of compounds 3−6 are consistent with the assigned structures (see experimental section).

In the next step, we tried to construct fused thiopyranthiones 7−10 from compounds 3−6 and carbon disulfide23−25 (Scheme 2). To optimize the yield of 7−10, we carried out several experiments on 3−6, testing different reaction conditions, e.g. solvent, time, and substrate/base molar ratio. Solvent effects were observed with THF giving the highest yield of fused thiopyranthiones, while other solvents such as CH2Cl2, hexane, and toluene gave very low yields of fused thiopyranthiones. The results are summarized in Table 2. As a consequence, the reaction of heterocyclic α,β-unsaturated nitriles 3a−c, 4a−d, 5a−c, and 6a−d with carbon disulfide in the presence of sodium hydride in THF at room temperature for 4 h led to the corresponding 6-thioxothieno[3,2-c]thiopyran and 6-thioxothiopyrano[4,3-b]furan derivatives 7a−c, 8a−d, 9a−c, and 10a−d in 24−72% yields. These products 7−10 gave satisfactory elemental analyses and spectroscopic data (IR, 1H NMR, 13C NMR, and MS) consistent with their assigned structures (see experimental section). For example, the IR spectra of 7−10 display bands in the range of 3430−3130 cm-1 due to a primary amino group. The 1H NMR spectra of 7−10 exhibit a D2O exchangeable signal near δ 6.0 attributable to the primary amino protons. The 13C NMR spectra of 7−10 show a signal near δ 180.5 due to the thiocarbonyl carbon. The formation of the fused thiopyranthiones 7−10 could be explained by possible mechanism presented in Scheme 2. It is conceivable that the initial event is the formation of the 1:1 adducts A from compounds 3−6 and carbon disulfide, which underwent intramolecular cyclization to result in the formation of 7−10.

Finally, we also attempted Gewald reaction26,27 of compounds 3, 5 and 6 with sulfur powder (Scheme 2). Having optimized the Gewald reaction parameters, we then examined several reaction conditions. The best results are shown in Table 3. Indeed, when a mixture of 3a−c, 5a−c, or 6a−d and sulfur powder in the presence of triethylamine in methanol was stirred at room temperature for 24 h, the corresponding thieno[3,4-b]thiophene and thieno[3,4-b]furan derivatives 11a−c, 12a−c, and 13a−d were obtained in moderate yields. In this case, the reaction of 4a−d with sulfur powder failed to give the expected thieno[3,4-b]furans and the reaction was not clean. The reason for this change of behavior is not very clear at present. The structures of compounds 11−13 were deduced from their elemental analyses, 1H NMR, and 13C NMR spectra (see experimental section). The IR spectra of 11−13 display bands in the range of 3470−3170 cm-1 due to a primary amino group. The 1H NMR spectra of 11−13 exhibit a D2O exchangeable signal near δ 6.5 attributable to the primary amino protons. A plausible mechanism for the formation of the fused thiophenes 11−13 is shown in Scheme 2. Compounds 3, 5 and 6 would be thiolated at the methylene carbon by sulfur, followed by ring closure to afford 11−13.

In conclusion, we have developed a simple and efficient method for the synthesis of 6-thioxothieno[3,2-c]thiopyran, 6-thioxothiopyrano[4,3-b]furan, thieno[3,4-b]thiophene, and thieno[3,4-b]furan derivatives 7−13 by the reactions of heterocyclic α,β-unsaturated nitriles 3−6 as one of versatile starting materials with carbon disulfide and/or sulfur powder in the presence of sodium hydride or triethylamine. This methodology offers significant advantages with regard to the simplicity of operation. Functionalized fused thiopyranthione and thiophene derivatives are important synthons in organic synthesis and for the preparation of biologically active compounds with interest in medicinal chemistry.

EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded on a JASCO FT/IR-4100 spectrometer. The 1H and 13C NMR spectra were measured with a JEOL JNM-A500 spectrometer at 500.00 and 125.65 MHz, respectively. The 1H and 13C chemical sifts (δ) are reported in parts per million (ppm) relative to TMS as internal standard. Positive FAB MS spectra were obtained on a JEOL JMS-700T spectrometer. Elemental analyses were performed on YANACO MT-6 CHN analyzer. The starting compounds, heterocyclic α,β-unsaturated nitriles 3−6, were prepared in this laboratory according to the procedure for the preparation of 3a and 4a reported in literature.22
General procedure for the preparation of heterocyclic α,β-unsaturated nitriles 3−6 from 1 and/or 2 and alkylidene phosphoranes.
A mixture of 1a−c and/or 2a−d (20 mmol) and (triphenylphosphoranylidene)acetonitrile (7.83 g, 26 mmol) or methyl (triphenylphosphoranylidene)acetate (7.36 g, 22 mmol) in toluene (20 mL) was refluxed for 8 h. After removal of the solvent in vacuo, Et2O (40 mL) was added to the residue. The solid was removed by filtration and washed with Et2O. The combined filtrates were concentrated in vacuo. The residue was purified by column chromatography on silica gel with CH2Cl2 as the eluent to afford 3a−c, 4a−d, 5a−c, and 6a−d.
3-Cyano-4,5-dihydro-4-phenyl-2-thiopheneacetonitrile (3b)
Colorless prisms (4.33 g, 96%), mp 68−69 °C (Et2O); IR (KBr): 2253, 2207 (CN) cm-1; 1H NMR (CDCl3): δ 3.45 (dd, J = 7.6, 11.7 Hz, 1H, 5-H), 3.66−3.76 (m, 2H, CH2CN), 3.88 (dd, J = 9.9, 11.7 Hz, 1H, 5-H), 4.49−4.54 (m, 1H, 4-H), 7.27−7.43 (m, 5H, aryl H); 13C NMR (CDCl3): δ 19.7 (CH2CN), 40.9 (C-5), 54.9 (C-4), 108.8 (C-3), 113.9 (CH2CN), 114.0 (CN), 127.1, 128.5, 129.4, 138.8 (C aryl), 152.2 (C-2); MS: m/z 227 [M+H]+. Anal. Calcd for C13H10N2S: C, 69.00; H, 4.45; N, 12.38. Found: C, 69.04; H, 4.56; N, 12.34.
3-Cyano-4,5-dihydro-5-methyl-2-thiopheneacetonitrile (3c)
Red oil (3.21 g, 98%); IR (neat): 2256, 2210 (CN) cm-1; 1H NMR (CDCl3): δ 1.46 (d, J = 6.7 Hz, 3H, CH3), 2.74 (tdd, J = 1.4, 6.1, 15.9 Hz, 1H, 4-H), 3.23 (tdd, J = 1.7, 8.9, 15.9 Hz, 1H, 4-H), 3.58−3.68 (m, 2H, CH2CN), 4.01−4.09 (m, 1H, 5-H); 13C NMR (CDCl3): δ 19.5 (CH2CN), 22.0 (CH3), 44.4 (C-4), 45.8 (C-5), 102.7 (C-3), 114.0 (CH2CN), 114.3 (CN), 151.2 (C-2); MS: m/z 165 [M+H]+. Anal. Calcd for C8H8N2S: C, 58.51; H, 4.91; N, 17.06. Found: C, 58.37; H, 4.97; N, 16.90.
3-Cyano-4,5-dihydro-4-phenyl-2-furanacetonitrile (4b)
Red oil (2.91 g, 69%); IR (neat): 2265, 2214 (CN) cm-1; 1H NMR (CDCl3): δ 3.55−3.64 (m, 2H, CH2CN), 4.40−4.44 (m, 1H, 4-H), 4.53−4.57 (m, 1H, 5-H), 4.95−5.00 (m, 1H, 5-H), 7.20−7.43 (m, 5H, aryl H); 13C NMR (CDCl3): δ 17.4 (CH2CN), 49.0 (C-4), 80.4 (C-5), 91.6 (C-3), 112.6 (CH2CN), 113.8 (CN), 127.1, 128.4, 129.4, 138.9 (C aryl), 161.4 (C-2); MS: m/z 211 [M+H]+. Anal. Calcd for C13H10N2O: C, 74.27; H, 4.79; N, 13.32. Found: C, 74.30; H, 4.94; N, 13.05.
3-Cyano-4,5-dihydro-5-methyl-2-furanacetonitrile (4c)
Red oil (2.88 g, 97%); IR (neat): 2263, 2214 (CN) cm-1; 1H NMR (CDCl3): δ 1.39 (d, J = 6.1 Hz, 3H, CH3), 2.46−2.52 (m, 1H, 4-H), 2.99−3.05 (m, 1H, 4-H), 3.41−3.42 (m, 2H, CH2CN), 4.92−4.98 (m, 1H, 5-H); 13C NMR (CDCl3): δ 17.3 (CH2CN), 21.4 (CH3), 37.3 (C-4), 82.2 (C-5), 85.1 (C-3), 112.7 (CH2CN), 114.6 (CN), 160.4 (C-2); MS: m/z 149 [M+H]+. Anal. Calcd for C8H8N2O: C, 64.85; H, 5.44; N, 18.91. Found: C, 64.73; H, 5.51; N, 18.64.
3-Cyano-4,5-dihydro-5-phenyl-2-furanacetonitrile (4d)
Red oil (3.12 g, 74%); IR (neat): 2261, 2215 (CN) cm-1; 1H NMR (CDCl3): δ 2.89−2.95 (m, 1H, 4-H), 3.28−3.35 (m, 1H, 4-H), 3.49−3.51 (m, 2H, CH2CN), 5.74−5.78 (m, 1H, 5-H), 7.17−7.37 (m, 5H, aryl H); 13C NMR (CDCl3): δ 17.3 (CH2CN), 38.2 (C-4), 85.6 (C-3), 86.1 (C-5), 112.6 (CH2CN), 114.1 (CN), 125.6, 129.05, 129.13, 138.8 (C aryl), 160.4 (C-2); MS: m/z 211 [M+H]+. Anal. Calcd for C13H10N2O: C, 74.27; H, 4.79; N, 13.32. Found: C, 74.38; H, 4.96; N, 13.12.
Methyl 3-cyano-4,5-dihydro-2-thiopheneacetate (5a)
Pale yellow oil (2.37 g, 65%); IR (neat): 2207 (CN), 1743 (C=O) cm-1; 1H NMR (CDCl3): δ 3.06 (tt, J = 1.4, 8.9 Hz, 2H, 4-H), 3.39 (t, J = 8.9 Hz, 2H, 5-H), 3.58 (t, J = 1.4 Hz, 2H, CH2CO2Me), 3.75 (s, 3H, CO2Me); 13C NMR (CDCl3): δ 32.9 (C-5), 35.9 (CH2CO2Me), 36.4 (C-4), 52.5 (CO2Me), 103.3 (C-3), 115.2 (CN), 156.1 (C-2), 168.0 (C=O); MS: m/z 184 [M+H]+. Anal. Calcd for C8H9NO2S: C, 52.44; H, 4.95; N, 7.64. Found: C, 52.53; H, 5.01; N, 7.74.
Methyl 3-cyano-4,5-dihydro-4-phenyl-2-thiopheneacetate (5b)
Colorless prisms (4.55 g, 88%), mp 79−80 °C (Et2O); IR (KBr): 2207 (CN), 1737 (C=O) cm-1; 1H NMR (CDCl3): δ 3.35 (dd, J = 7.0, 11.6 Hz, 1H, 5-H), 3.62−3.71 (m, 2H, CH2CO2Me), 3.78 (s, 3H, CO2Me), 3.82 (dd, J = 10.1, 11.6 Hz, 1H, 5-H), 4.45−4.50 (m, 1H, 4-H), 7.29−7.40 (m, 5H, aryl H); 13C NMR (CDCl3): δ 36.1 (CH2CO2Me), 41.0 (C-5), 52.6 (CO2Me), 54.6 (C-4), 108.0 (C-3), 115.1 (CN), 127.2, 128.2, 129.2, 139.6 (C aryl), 156.5 (C-2), 168.0 (C=O); MS: m/z 260 [M+H]+. Anal. Calcd for C14H13NO2S: C, 64.84; H, 5.05; N, 5.40. Found: C, 64.92; H, 5.11; N, 5.38.
Methyl 3-cyano-4,5-dihydro-5-methyl-2-thiopheneacetate (5c)
Yellow oil (3.72 g, 94%); IR (neat): 2206 (CN), 1744 (C=O) cm-1; 1H NMR (CDCl3): δ 1.42 (d, J = 6.7 Hz, 3H, CH3), 2.70 (tdd, J = 1.2, 5.8, 15.6 Hz, 1H, 4-H), 3.18 (tdd, J = 1.4, 8.5, 15.6 Hz, 1H, 4-H), 3.56−3.58 (m, 2H, CH2CO2Me), 3.75 (s, 3H, CO2Me), 3.89−3.99 (m, 1H, 5-H); 13C NMR (CDCl3): δ 22.0 (CH3), 36.1 (CH2CO2Me), 44.2 (C-4), 45.4 (C-5), 52.5 (CO2Me), 101.8 (C-3), 115.4 (CN), 155.3 (C-2), 168.1 (C=O); MS: m/z 198 [M+H]+. Anal. Calcd for C9H11NO2S: C, 54.80; H, 5.62; N, 7.10. Found: C, 54.86; H, 5.52; N, 7.01.
Methyl 3-cyano-4,5-dihydro-2-furanacetate (6a)
Colorless oil (1.85 g, 55%); IR (neat): 2211 (CN), 1746 (C=O) cm-1; 1H NMR (CDCl3): δ 2.92−2.98 (m, 2H, 4-H), 3.42−3.43 (m, 2H, CH2CO2Me), 3.75 (s, 3H, CO2Me), 4.55−4.60 (m, 2H, 5-H); 13C NMR (CDCl3): δ 30.3 (C-4), 33.5 (CH2CO2Me), 52.6 (CO2Me), 72.2 (C-5), 85.3 (C-3), 115.7 (CN), 166.3 (C-2), 167.1 (C=O); MS: m/z 168 [M+H]+. Anal. Calcd for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.50; H, 5.31; N, 8.40.
Methyl 3-cyano-4,5-dihydro-4-phenyl-2-furanacetate (6b)
Colorless prisms (3.74 g, 77%), mp 46−47 °C (Et2O); IR (KBr): 2212 (CN), 1739 (C=O) cm-1; 1H NMR (CDCl3): δ 3.48−3.58 (m, 2H, CH2CO2Me), 3.78 (s, 3H, CO2Me), 4.37 (dd, J = 6.4, 10.5 Hz, 1H, 4-H), 4.46 (dd, J = 6.4, 9.4 Hz, 1H, 5-H), 4.90 (dd, J = 9.4, 10.5 Hz, 1H, 5-H), 7.24−7.27 (m, 2H, aryl H), 7.28−7.32 (m, 1H, aryl H), 7.35−7.39 (m, 2H, aryl H); 13C NMR (CDCl3): δ 33.7 (CH2CO2Me), 48.9 (C-4), 52.7 (CO2Me), 80.1 (C-5), 91.0 (C-3), 115.1 (CN), 127.2, 128.0, 129.2, 140.0 (C aryl), 166.5 (C-2), 167.1 (C=O); MS: m/z 244 [M+H]+. Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.21; H, 5.47; N, 5.77.
Methyl 3-cyano-4,5-dihydro-5-methyl-2-furanacetate (6c)
Pale yellow oil (3.02 g, 83%); IR (neat): 2210 (CN), 1747 (C=O) cm-1; 1H NMR (CDCl3): δ 1.41 (d, J = 6.1 Hz, 3H, CH3), 2.49−2.55 (m, 1H, 4-H), 3.02−3.09 (m, 1H, 4-H), 3.40 (dd, J = 1.2, 2.1 Hz, 2H, CH2CO2Me), 3.75 (s, 3H, CO2Me), 4.91−4.97 (m, 1H, 5-H); 13C NMR (CDCl3): δ 21.4 (CH3), 33.7 (CH2CO2Me), 37.2 (C-4), 52.5 (CO2Me), 81.3 (C-5), 84.3 (C-3), 115.9 (CN), 165.4 (C-2), 167.2 (C=O); MS: m/z 182 [M+H]+. Anal. Calcd for C9H11NO3•0.1H2O: C, 59.07; H, 6.17; N, 7.65. Found: C, 59.20; H, 6.04; N, 7.64.
Methyl 3-cyano-4,5-dihydro-5-phenyl-2-furanacetate (6d)
Pale yellow oil (4.28 g, 88%); IR (neat): 2211 (CN), 1747 (C=O) cm-1; 1H NMR (CDCl3): δ 2.91−2.96 (m, 1H, 4-H), 3.33−3.40 (m, 1H, 4-H), 3.46−3.55 (m, 2H, CH2CO2Me), 3.76 (s, 3H, CO2Me), 5.73−5.78 (m, 1H, 5-H), 7.32−7.42 (m, 5H, aryl H); 13C NMR (CDCl3): δ 33.7 (CH2CO2Me), 38.4 (C-4), 52.6 (CO2Me), 84.7 (C-3), 85.5 (C-5), 115.5 (CN), 125.7, 128.8, 128.9, 139.9 (C aryl), 165.5 (C-2), 167.1 (C=O); MS: m/z 244 [M+H]+. Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.09; H, 5.45; N, 5.77.
General procedure for the preparation of fused thiopyranthiones 7−10 from 3−6 and carbon disulfide in the presence of sodium hydride.
To an ice-cooled and stirred solution of 3a−c, 4a−d, 5a−c, and 6a−d (5 mmol) in THF (5 mL) was added 60% NaH (0.20 g, 5 mmol). The stirring was continued at rt until evolution of gas ceased. To the obtained mixture was added carbon disulfide (0.42 g, 5.5 mmol) with stirring and then the mixture was stirred at rt for 4 h. The reaction mixture was neutralized with acetic acid (0.30 g, 5 mmol) with stirring and ice-cooling. After removal of the solvent in vacuo, cold water was added to the residue. Further processing of the resulting mixture is described in the following paragraphs.
(A) The precipitate was isolated by filtration, washed with water, dried, and recrystallized from an appropriate solvent to give 7a−c, 8a−d, 9a, and 10a.
(B) The resulting mixture was extracted with CH2Cl2. The extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on alumina with CH2Cl2-acetone (4:1) as the eluent to afford 9b−c and 10b−d.
4-Amino-2,3-dihydro-6-thioxo-6H-thieno[3,2-c]thiopyran-7-carbonitrile (7a)
Pale yellow prisms (0.75 g, 66%), mp >300 °C (DMSO/H2O); IR (KBr): 3427, 3311, 3207, 3140 (NH), 2200 (CN) cm-1; 1H NMR (DMSO-d6): δ 3.17 (t, J = 8.4 Hz, 2H, 3-H), 3.53 (t, J = 8.4 Hz, 2H, 2-H), 8.77 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 31.9 (C-2), 33.4 (C-3), 101.0 (C-7), 113.3 (C-3a), 116.7 (CN), 161.6 (C-4), 167.8 (C-7a), 187.2 (C=S); MS: m/z 227 [M+H]+. Anal. Calcd for C8H6N2S3: C, 42.45; H, 2.67; N, 12.38. Found: C, 42.36; H, 2.82; N, 12.14.
4-Amino-2,3-dihydro-3-phenyl-6-thioxo-6H-thieno[3,2-c]thiopyran-7-carbonitrile (7b)
Orange prisms (0.60 g, 40%), mp 237−238 °C (acetone/petroleum ether); IR (KBr): 3384, 3292, 3184 (NH), 2210 (CN) cm-1; 1H NMR (DMSO-d6): δ 3.26 (dd, J = 0.9, 11.6 Hz, 1H, 2-H), 4.09 (dd, J = 8.4, 11.6 Hz, 1H, 2-H), 4.89−4.92 (m, 1H, 3-H), 7.21−7.24 (m, 2H, aryl H), 7.26−7.31 (m, 1H, aryl H), 7.33−7.37 (m, 2H, aryl H), 8.65 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 41.7 (C-2), 49.1 (C-3), 101.2 (C-7), 115.1 (C-3a), 116.6 (CN), 126.8, 127.3, 128.6, 139.5 (C aryl), 162.4 (C-4), 168.6 (C-7a), 187.8 (C=S); MS: m/z 303 [M+H]+. Anal. Calcd for C14H10N2S3: C, 55.60; H, 3.33; N, 9.26. Found: C, 55.51; H, 3.52; N, 9.02.
4-Amino-2,3-dihydro-2-methyl-6-thioxo-6H-thieno[3,2-c]thiopyran-7-carbonitrile (7c)
Yellow prisms (0.29 g, 24%), mp 280 °C (dec.) (acetone); IR (KBr): 3378, 3303, 3161 (NH), 2212 (CN) cm-1; 1H NMR (DMSO-d6): δ 1.42 (d, J = 6.7 Hz, 3H, CH3), 2.86 (dd, J = 5.6, 15.4 Hz, 1H, 3-H), 3.28−3.34 (m, 1H, 3-H), 4.13−4.21 (m, 1H, 2-H), 8.78 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 22.2 (CH3), 41.1 (C-3), 44.5 (C-2), 101.0 (C-7), 112.2 (C-3a), 116.6 (CN), 162.0 (C-4), 166.7 (C-7a), 187.1 (C=S); MS: m/z 241 [M+H]+. Anal. Calcd for C9H8N2S3 · 0.1 H2O: C, 44.64; H, 3.41; N, 11.57. Found: C, 44.48; H, 3.44; N, 11.41.
4-Amino-2,3-dihydro-6-thioxo-6H-thiopyrano[4,3-b]furan-7-carbonitrile (8a)
Pale yellow prisms (0.50 g, 47%), mp 276 °C (dec.) (DMSO/H2O); IR (KBr): 3386, 3277, 3177 (NH), 2213 (CN) cm-1; 1H NMR (DMSO-d6): δ 2.98 (t, J = 8.9 Hz, 2H, 3-H), 4.83 (t, J = 8.9 Hz, 2H, 2-H), 8.67 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 26.8 (C-3), 74.8 (C-2), 94.1 (C-7), 102.4 (C-3a), 114.5 (CN), 163.1 (C-4), 173.6 (C-7a), 190.3 (C=S); MS: m/z 211 [M+H]+. Anal. Calcd for C8H6N2OS2·0.2H2O: C, 44.93; H, 3.02; N, 13.10. Found: C, 44.97; H, 2.97; N, 13.06.
4-Amino-2,3-dihydro-3-phenyl-6-thioxo-6H-thiopyrano[4,3-b]furan-7-carbonitrile (8b)
Pale yellow needles (0.95 g, 66%), mp 230−231 °C (acetone/petroleum ether); IR (KBr): 3418, 3294, 3183 (NH), 2222 (CN) cm-1; 1H NMR (DMSO-d6): δ 4.63 (dd, J = 3.1, 9.0 Hz, 1H, 3-H), 4.66 (dd, J = 3.1, 9.0 Hz, 1H, 2-H), 5.12 (t, J = 9.0 Hz, 1H, 2-H), 7.20−7.24 (m, 2H, aryl H), 7.26−7.30 (m, 1H, aryl H), 7.33−7.37 (m, 2H, aryl H), 8.49 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 44.0 (C-3), 82.5 (C-2), 94.1 (C-7), 105.3 (C-3a), 114.4 (CN), 126.9, 127.3, 128.7, 140.2 (C aryl), 163.9 (C-4), 173.6 (C-7a), 191.0 (C=S); MS: m/z 287 [M+H]+. Anal. Calcd for C14H10N2OS2: C, 58.72; H, 3.52; N, 9.78. Found: C, 58.59; H, 3.62; N, 9.71.
4-Amino-2,3-dihydro-2-methyl-6-thioxo-6H-thiopyrano[4,3-b]furan-7-carbonitrile (8c)
Pale yellow needles (0.73 g, 65%), mp 286 °C (dec.) (acetone/petroleum ether); IR (KBr): 3306, 3172 (NH), 2222 (CN) cm-1; 1H NMR (DMSO-d6): δ 1.47 (d, J = 6.4 Hz, 3H, CH3), 2.56 (dd, J = 7.2, 14.9 Hz, 1H, 3-H), 3.51 (dd, J = 9.2, 14.9 Hz, 1H, 3-H), 5.23−5.30 (m, 1H, 2-H), 8.64 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 21.2 (CH3), 33.7 (C-3), 84.3 (C-2), 94.0 (C-7), 102.1 (C-3a), 114.6 (CN), 163.2 (C-4), 172.7 (C-7a), 190.3 (C=S); MS: m/z 225 [M+H]+. Anal. Calcd for C9H8N2OS2: C, 48.19; H, 3.59; N, 12.49. Found: C, 48.24; H, 3.63; N, 12.23.
4-Amino-2,3-dihydro-2-phenyl-6-thioxo-6H-thiopyrano[4,3-b]furan-7-carbonitrile (8d)
Pale yellow prisms (0.86 g, 60%), mp 264 °C (dec.) (acetone/petroleum ether); IR (KBr): 3340, 3263, 3142 (NH), 2216 (CN) cm-1; 1H NMR (DMSO-d6): δ 2.94 (dd, J = 7.5, 15.2 Hz, 1H, 3-H), 3.50 (dd, J = 9.7, 15.2 Hz, 1H, 3-H), 6.17 (dd, J = 7.5, 9.7 Hz, 1H, 2-H), 7.39−7.48 (m, 5H, aryl H), 8.76 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 34.8 (C-3), 87.4 (C-2), 93.8 (C-7), 101.6 (C-3a), 114.5 (CN), 126.2, 128.8, 128.9, 139.2 (C aryl), 163.3 (C-4), 172.4 (C-7a), 190.6 (C=S); MS: m/z 287 [M+H]+. Anal. Calcd for C14H10N2OS2: C, 58.72; H, 3.52; N, 9.78. Found: C, 58.62; H, 3.71; N, 9.59.
Methyl 4-amino-2,3-dihydro-6-thioxo-6H-thieno[3,2-c]thiopyran-7-carboxylate (9a)
Pale yellow prisms (0.69 g, 53%), mp 214 °C (dec.) (acetone); IR (KBr): 3392, 3302, 3188 (NH), 1697 (C=O) cm-1; 1H NMR (DMSO-d6): δ 3.08 (t, J = 8.1 Hz, 2H, 3-H), 3.38 (t, J = 8.1 Hz, 2H, 2-H), 3.70 (s, 3H, CO2Me), 8.21 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 31.7 (C-2), 32.6 (C-3), 51.8 (CO2Me), 112.3 (C-3a), 123.6 (C-7), 160.7 (C-4), 162.5 (C-7a), 166.9 (C=O), 181.9 (C=S); MS: m/z 260 [M+H]+. Anal. Calcd for C9H9NO2S3: C, 41.68; H, 3.50; N, 5.40. Found: C, 41.70; H, 3.57; N, 5.21.
Methyl 4-amino-2,3-dihydro-3-phenyl-6-thioxo-6H-thieno[3,2-c]thiopyran-7-carboxylate (9b)
Yellow prisms (0.89 g, 53%), mp 194 °C (dec.) (acetone/petroleum ether); IR (KBr): 3400, 3308, 3205 (NH), 1717 (C=O) cm-1; 1H NMR (DMSO-d6): δ 3.15 (dd, J = 1.2, 11.5 Hz, 1H, 2-H), 3.72 (s, 3H, CO2Me), 3.93 (dd, J = 8.2, 11.5 Hz, 1H, 2-H), 4.82−4.84 (m, 1H, 3-H), 7.20−7.23 (m, 2H, aryl H), 7.25−7.29 (m, 1H, aryl H), 7.33−7.37 (m, 2H, aryl H), 8.09 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 41.2 (C-2), 48.2 (C-3), 51.9 (CO2Me), 114.2 (C-3a), 123.6 (C-7), 126.8, 127.2, 128.4, 139.9 (C aryl), 161.6 (C-4), 163.1 (C-7a), 166.9 (C=O), 182.8 (C=S); MS: m/z 336 [M+H]+. Anal. Calcd for C15H13NO2S3: C, 53.70; H, 3.91; N, 4.18. Found: C, 53.84; H, 3.96; N, 4.14.
Methyl 4-amino-2,3-dihydro-2-methyl-6-thioxo-6H-thieno[3,2-c]thiopyran-7-carboxylate (9c)
Yellow prisms (0.61 g, 45%), mp 169 °C (dec.) (acetone/petroleum ether); IR (KBr): 3342, 3287, 3145 (NH), 1714 (C=O) cm-1; 1H NMR (DMSO-d6): δ 1.36 (d, J = 6.7 Hz, 3H, CH3), 2.78 (dd, J = 6.0, 15.4 Hz, 1H, 3-H), 3.23 (dd, J = 8.1, 15.4 Hz, 1H, 3-H), 3.69 (s, 3H, CO2Me), 3.99−4.06 (m, 1H, 2-H), 8.20 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 21.9 (CH3), 40.4 (C-3), 43.9 (C-2), 51.9 (CO2Me), 111.4 (C-3a), 123.6 (C-7), 161.2 (C-4), 161.6 (C-7a), 166.9 (C=O), 181.8 (C=S); MS: m/z 274 [M+H]+. Anal. Calcd for C10H11NO2S3: C, 43.93; H, 4.06; N, 5.12. Found: C, 43.99; H, 4.10; N, 5.08.
Methyl 4-amino-2,3-dihydro-6-thioxo-6H-thiopyrano[4,3-b]furan-7-carboxylate (10a)
Colorless plates (0.88 g, 72%), mp 190 °C (dec.) (methanol); IR (KBr): 3379, 3303, 3184 (NH), 1698 (C=O) cm-1; 1H NMR (DMSO-d6): δ 2.93 (t, J = 8.7 Hz, 2H, 3-H), 3.68 (s, 3H, CO2Me), 4.71 (t, J = 8.7 Hz, 2H, 2-H), 8.17 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 26.4 (C-3), 51.9 (CO2Me), 73.8 (C-2), 101.7 (C-3a), 116.0 (C-7), 162.5 (C-4), 165.1 (C=O), 169.5 (C-7a), 184.2 (C=S); MS: m/z 244 [M+H]+. Anal. Calcd for C9H9NO3S2: C, 44.43; H, 3.73; N, 5.76. Found: C, 44.42; H, 3.76; N, 5.67.
Methyl 4-amino-2,3-dihydro-3-phenyl-6-thioxo-6H-thiopyrano[4,3-b]furan-7-carboxylate (10b)
Pale yellow prisms (0.82 g, 52%), mp 208 °C (dec.) (acetone/petroleum ether); IR (KBr): 3366, 3280, 3140 (NH), 1719 (C=O) cm-1; 1H NMR (DMSO-d6): δ 3.71 (s, 3H, CO2Me), 4.50 (dd, J = 2.9, 9.1 Hz, 1H, 2-H), 4.61 (dd, J = 2.9, 9.1 Hz, 1H, 3-H), 4.99 (t, J = 9.1 Hz, 1H, 2-H), 7.17−7.20 (m, 2H, aryl H), 7.25−7.29 (m, 1H, aryl H), 7.33−7.37 (m, 2H, aryl H), 7.99 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 43.6 (C-3), 52.0 (CO2Me), 81.6 (C-2), 104.7 (C-3a), 116.0 (C-7), 126.8, 127.1, 128.7, 140.6 (C aryl), 163.3 (C-4), 165.0 (C=O), 169.4 (C-7a), 185.1 (C=S); MS: m/z 320 [M+H]+. Anal. Calcd for C15H13NO3S2: C, 56.41; H, 4.10; N, 4.39. Found: C, 56.38; H, 4.10; N, 4.35.
Methyl 4-amino-2,3-dihydro-2-methyl-6-thioxo-6H-thiopyrano[4,3-b]furan-7-carboxylate (10c)
Pale yellow prisms (0.49 g, 38%), mp 182 °C (dec.) (acetone/petroleum ether); IR (KBr): 3330, 3303, 3167 (NH), 1699 (C=O) cm-1; 1H NMR (DMSO-d6): δ 1.39 (d, J = 6.1 Hz, 3H, CH3), 2.51 (dd, J = 7.0, 15.0 Hz, 1H, 3-H), 3.10 (dd, J = 8.9, 15.0 Hz, 1H, 3-H), 3.68 (s, 3H, CO2Me), 5.08−5.16 (m, 1H, 2-H), 8.13 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 21.3 (CH3), 33.4 (C-3), 51.9 (CO2Me), 83.0 (C-2), 101.4 (C-3a), 116.0 (C-7), 162.5 (C-4), 165.1 (C=O), 168.6 (C-7a), 184.1 (C=S); MS: m/z 258 [M+H]+. Anal. Calcd for C10H11NO3S2: C, 46.67; H, 4.31; N, 5.44. Found: C, 46.71; H, 4.32; N, 5.39.
Methyl 4-amino-2,3-dihydro-2-phenyl-6-thioxo-6H-thiopyrano[4,3-b]furan-7-carboxylate (10d)
Pale yellow needles (0.59 g, 37%), mp 199 °C (dec.) (acetone/petroleum ether); IR (KBr): 3315, 3138 (NH), 1706 (C=O) cm-1; 1H NMR (DMSO-d6): δ 2.87 (dd, J = 6.8, 15.3 Hz, 1H, 3-H), 3.46 (dd, J = 9.5, 15.3 Hz, 1H, 3-H), 3.68 (s, 3H, CO2Me), 6.06 (dd, J = 6.8, 9.5 Hz, 1H, 2-H), 7.34−7.45 (m, 5H, aryl H), 8.24 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 34.7 (C-3), 52.0 (CO2Me), 86.0 (C-2), 100.7 (C-3a), 115.8 (C-7), 125.6, 128.5, 128.7, 140.0 (C aryl), 162.7 (C-4), 165.1 (C=O), 168.5 (C-7a), 184.6 (C=S); MS: m/z 320 [M+H]+. Anal. Calcd for C15H13NO3S2: C, 56.41; H, 4.10; N, 4.39. Found: C, 56.32; H, 4.08; N, 4.33.
General procedure for the preparation of fused thiophenes 11−13 from 3, 5 and/or 6 and sulfur powder in the presence of triethylamine.
A mixture of 3a−c, 5a−c, and/or 6a−d (5 mmol), sulfur powder (0.16 g, 5 mmol), and triethylamine (1.45 g, 14.3 mmol) in MeOH (5 mL) was stirred at rt for 24 h. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel with CH2Cl2 as the eluent to yield 11a−c,
12a−c, and 13a−d.
4-Amino-2,3-dihydrothieno[3,4-b]thiophene-6-carbonitrile (11a)
Pale yellow columns (1.32 g, 51%), mp 125−126 °C (Et2O); IR (KBr): 3338, 3295, 3198 (NH), 2194 (CN) cm-1; 1H NMR (DMSO-d6): δ 2.81 (t, J = 7.5 Hz, 2H, 3-H), 3.79 (t, J = 7.5 Hz, 2H, 2-H), 6.68 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 27.3 (C-3), 40.6 (C-2), 73.1 (C-6), 115.9 (CN), 120.4 (C-3a), 150.5 (C-4), 155.1 (C-6a); MS: m/z 183 [M+H]+. Anal. Calcd for C7H6N2S2: C, 46.13; H, 3.32; N, 15.37. Found: C, 46.06; H, 3.38; N, 15.31.
4-Amino-2,3-dihydro-3-phenylthieno[3,4-b]thiophene-6-carbonitrile (11b)
Colorless prisms (0.55 g, 43%), mp 137−138 °C (Et2O/petroleum ether); IR (KBr): 3399, 3325, 3220 (NH), 2189 (CN) cm-1; 1H NMR (DMSO-d6): δ 3.54 (dd, J = 2.4, 11.3 Hz, 1H, 2-H), 4.37 (dd, J = 7.9, 11.3 Hz, 1H, 2-H), 4.47 (dd, J = 2.4, 7.9 Hz, 1H, 3-H), 6.53 (br s, 2H, NH2), 7.20−7.26 (m, 3H, aryl H), 7.30−7.34 (m, 2H, aryl H); 13C NMR (DMSO-d6): δ 44.1 (C-3), 49.4 (C-2), 73.3 (C-6), 115.8 (CN), 122.1 (C-3a), 126.8, 127.0, 128.3, 141.2 (C aryl), 151.8 (C-4), 155.1 (C-6a); MS: m/z 259 [M+H]+. Anal. Calcd for C13H10N2S2: C, 60.43; H, 3.90; N, 10.84. Found: C, 60.55; H, 4.02; N, 10.80.
4-Amino-2,3-dihydro-2-methylthieno[3,4-b]thiophene-6-carbonitrile (11c)
Colorless prisms (0.70 g, 71%), mp 69−71 °C (Et2O/petroleum ether); IR (KBr): 3307, 3187 (NH), 2198 (CN) cm-1; 1H NMR (DMSO-d6): δ 1.44 (d, J = 6.7 Hz, 3H, CH3), 2.48 (dd, J = 6.4, 15.0 Hz, 1H, 3-H), 2.99 (dd, J = 7.5, 15.0 Hz, 1H, 3-H), 4.44−4.51 (m, 1H, 2-H), 6.67 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 22.4 (CH3), 35.7 (C-3), 54.1 (C-2), 73.3 (C-6), 115.9 (CN), 119.2 (C-3a), 150.9 (C-4), 154.2 (C-6a); MS: m/z 197 [M+H]+. Anal. Calcd for C8H8N2S2: C, 48.95; H, 4.11; N, 14.27. Found: C, 49.03; H, 4.11; N, 14.20.
Methyl 4-amino-2,3-dihydrothieno[3,4-b]thiophene-6-carboxylate (12a)
Colorless columns (0.97 g, 90%), mp 130−131 °C (acetone/petroleum ether); IR (KBr): 3423, 3321, 3204 (NH), 1651 (C=O) cm-1; 1H NMR (DMSO-d6): δ 2.76 (t, J = 7.8 Hz, 2H, 3-H), 3.63 (s, 3H, CO2Me), 3.64 (t, J = 7.8 Hz, 2H, 2-H), 6.46 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 26.5 (C-3), 39.1 (C-2), 50.8 (CO2Me), 96.5 (C-6), 120.9 (C-3a), 150.5 (C-4), 152.5 (C-6a), 161.9 (C=O); MS: m/z 216 [M+H]+. Anal. Calcd for C8H9NO2S2: C, 44.63; H, 4.21; N, 6.51. Found: C, 44.52; H, 4.20; N, 6.48.
Methyl 4-amino-2,3-dihydro-3-phenylthieno[3,4-b]thiophene-6-carboxylate (12b)
Colorless prisms (0.93 g, 64%), mp 151−152 °C (acetone/petroleum ether); IR (KBr): 3443, 3327, 3208 (NH), 1656 (C=O) cm-1; 1H NMR (DMSO-d6): δ 3.41 (dd, J = 2.6, 11.4 Hz, 1H, 2-H), 3.65 (s, 3H, CO2Me), 4.23 (dd, J = 8.2, 11.4 Hz, 1H, 2-H), 4.42 (dd, J = 2.6, 8.2 Hz, 1H, 3-H), 6.28 (br s, 2H, NH2), 7.20−7.24 (m, 3H, aryl H), 7.28−7.32 (m, 2H, aryl H); 13C NMR (DMSO-d6): δ 43.5 (C-3), 48.2 (C-2), 50.9 (CO2Me), 96.5 (C-6), 123.0 (C-3a), 126.6, 127.0, 128.3, 142.0 (C aryl), 151.8 (C-4), 152.4 (C-6a), 161.9 (C=O); MS: m/z 292 [M+H]+. Anal. Calcd for C14H13NO2S2: C, 57.71; H, 4.50; N, 4.81. Found: C, 57.94; H, 4.55; N, 4.77.
Methyl 4-amino-2,3-dihydro-2-methylthieno[3,4-b]thiophene-6-carboxylate (12c)
Colorless needles (0.35 g, 31%), mp 117−119 °C (acetone/petroleum ether); IR (KBr): 3448, 3313, 3204 (NH), 1671 (C=O) cm-1; 1H NMR (DMSO-d6): δ 1.40 (d, J = 6.7 Hz, 3H, CH3), 2.41 (dd, J = 6.4, 15.0 Hz, 1H, 3-H), 2.95 (dd, J = 7.6, 15.0 Hz, 1H, 3-H), 3.62 (s, 3H, CO2Me), 4.26−4.34 (m, 1H, 2-H), 6.44 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 22.7 (CH3), 35.1 (C-3), 50.8 (CO2Me), 51.9 (C-2), 96.6 (C-6), 119.8 (C-3a), 150.9 (C-4), 151.6 (C-6a), 161.8 (C=O); MS: m/z 230 [M+H]+. Anal. Calcd for C9H11NO2S2: C, 47.14; H, 4.83; N, 6.11. Found: C, 47.40; H, 4.90; N, 6.06.
Methyl 4-amino-2,3-dihydrothieno[3,4-b]furan-6-carboxylate (13a)
Colorless prisms (0.55 g, 55%), mp 173−174 °C (acetone/petroleum ether); IR (KBr): 3425, 3380 3323, 3206 (NH), 1660 (C=O) cm-1; 1H NMR (DMSO-d6): δ 2.75 (t, J = 8.2 Hz, 2H, 3-H), 3.57 (s, 3H, CO2Me), 4.89 (t, J = 8.2 Hz, 2H, 2-H), 6.54 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 24.6 (C-3), 50.3 (CO2Me), 80.2 (C-2), 82.4 (C-6), 108.9 (C-3a), 149.8 (C-4), 161.1 (C=O), 165.9 (C-6a); MS: m/z 200 [M+H]+. Anal. Calcd for C8H9NO3S: C, 48.23; H, 4.55; N, 7.03. Found: C, 48.27; H, 4.53; N, 7.01.
Methyl 4-amino-2,3-dihydro-3-phenylthieno[3,4-b]furan-6-carboxylate (13b)
Colorless needles (0.40 g, 29%), mp 152−154 °C (acetone/petroleum ether); IR (KBr): 3470, 3288, 3177 (NH), 1653 (C=O) cm-1; 1H NMR (DMSO-d6): δ 3.60 (s, 3H, CO2Me), 4.37 (dd, J = 3.7, 8.6 Hz, 1H, 3-H), 4.65 (dd, J = 3.7, 8.6 Hz, 1H, 2-H), 5.24 (t, J = 8.6 Hz, 1H, 2-H), 6.45 (br s, 2H, NH2), 7.17−7.20 (m, 2H, aryl H), 7.21−7.25 (m, 1H, aryl H), 7.30−7.35 (m, 2H, aryl H); 13C NMR (DMSO-d6): δ 42.7 (C-3), 50.4 (CO2Me), 82.5 (C-6), 87.9 (C-2), 111.6 (C-3a), 126.6, 126.9, 128.5, 141.8 (C aryl), 150.9 (C-4), 161.1 (C=O), 165.5 (C-6a); MS: m/z 276 [M+H]+. Anal. Calcd for C14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C, 61.18; H, 4.71; N, 5.09.
Methyl 4-amino-2,3-dihydro-2-methylthieno[3,4-b]furan-6-carboxylate (13c)
Colorless needles (0.27 g, 21%), mp 156−157 °C (acetone/petroleum ether); IR (KBr): 3432, 3330, 3216 (NH), 1658 (C=O) cm-1; 1H NMR (DMSO-d6): δ 1.41 (d, J = 6.4 Hz, 3H, CH3), 2.34 (dd, J = 7.2, 14.5 Hz, 1H, 3-H), 2.90 (dd, J = 8.4, 14.5 Hz, 1H, 3-H), 3.57 (s, 3H, CO2Me), 5.24−5.32 (m, 1H, 2-H), 6.51 (br s, 2H, NH2); 13C NMR (DMSO-d6): δ 21.9 (CH3), 32.2 (C-3), 50.3 (CO2Me), 82.4 (C-6), 89.6 (C-2), 108.5 (C-3a), 149.9 (C-4), 161.1 (C=O), 165.1 (C-6a); MS: m/z 214 [M+H]+. Anal. Calcd for C9H11NO3S: C, 50.69; H, 5.20; N, 6.57. Found: C, 50.69; H, 5.13; N, 6.52.
Methyl 4-amino-2,3-dihydro-2-phenylthieno[3,4-b]furan-6-carboxylate (13d)
Colorless prisms (0.91 g, 66%), mp 181−182 °C (acetone/petroleum ether); IR (KBr): 3453, 3330, 3206 (NH), 1663 (C=O) cm-1; 1H NMR (DMSO-d6): δ 2.69 (dd, J = 7.0, 14.6 Hz, 1H, 3-H), 3.25 (dd, J = 8.9, 14.6 Hz, 1H, 3-H), 3.58 (s, 3H, CO2Me), 6.18 (dd, J = 7.0, 8.9 Hz, 1H, 2-H), 6.61 (br s, 2H, NH2), 7.33−7.43 (m, 5H, aryl H); 13C NMR (DMSO-d6): δ 33.3 (C-3), 50.4 (CO2Me), 82.6 (C-6), 93.0 (C-2), 107.9 (C-3a), 125.8, 128.2, 128.5, 141.1 (C aryl), 150.1 (C-4), 161.1 (C=O), 164.8 (C-6a); MS: m/z 276 [M+H]+. Anal. Calcd for C14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C, 61.29; H, 4.77; N, 5.01.

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